RESUMEN
BACKGROUND: Traumatic brain injury (TBI) is a major cause of neurological disability, and current treatments have limited effectiveness. Recent studies have emphasized the potential of exosomes derived from umbilical cord mesenchymal stem cells (UC-MSCs-Exo) in TBI treatment, but the molecular mechanisms underlying their therapeutic effects are not fully understood. METHODS AND RESULTS: In this study, UC-MSCs-Exo was isolated using ultracentrifugation and intraventricularly injected to TBI rat model. The neurofunctional motor function of the rats was evaluated using the modified neurological severity score (mNSS), and the activation of microglia was assessed through immunofluorescence detection of IBA1 expression levels. Additionally, we established an in vitro neuroinflammatory model using BV2 microglia to investigate the effects of UC-MSCs-Exo and miRNA-21. Our findings indicate that UC-MSCs-Exo promote neurological recovery in TBI rats and inhibit excessive microglia activation. Furthermore, UC-MSCs-Exo highly expresses miRNA-21 and inhibited the proliferation, migration, and release of inflammatory mediators of BV2 microglia by transporting miRNA-21. CONCLUSIONS: The present study suggests that the promotion of neurological recovery in TBI rats by UC-MSCs-Exo may be attributed to the inhibition of excessive microglia activation through miRNA-21.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Modelos Animales de Enfermedad , Exosomas , Células Madre Mesenquimatosas , MicroARNs , Microglía , Cordón Umbilical , MicroARNs/genética , MicroARNs/metabolismo , Animales , Microglía/metabolismo , Células Madre Mesenquimatosas/metabolismo , Exosomas/metabolismo , Ratas , Cordón Umbilical/citología , Lesiones Traumáticas del Encéfalo/terapia , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/patología , Ratas Sprague-Dawley , Trasplante de Células Madre Mesenquimatosas/métodos , Masculino , Humanos , Proliferación Celular , Movimiento CelularRESUMEN
Traumatic brain injury (TBI) is a serious neurological disorder with increasing worldwide incidence. Emerging evidence has shown a significant therapeutic role of mesenchymal stem cells (MSCs) derived exosomes on traumatic brain injury with broad application prospects as a cell-free therapy. However, a comprehensive understanding of its underlying mechanism remained elusive. In this study, umbilical cord mesenchymal stem cells (UCMSCs)-derived exosomes (UC-MSCs-Exo) were isolated by ultracentrifugation and injected intraventricularly in a rat model of TBI. Our results showed that UC-MSCs-Exo promoted functional recovery and reduced neuronal apoptosis in TBI rats. Moreover, UC-MSCs-Exo inhibited the activation of microglia and astrocytes during brain injury, thereby promoting functional recovery. However, the effect of UC-MSCs-Exo on the content of plasma inflammatory factors in rats was not significant. Collectively our study suggested that UC-MSCs-Exo promotes the recovery of neurological function in TBI rats by inhibiting the activation of microglia and astrocytes, providing a theoretical basis for new therapeutic strategies for central nervous system diseases.
RESUMEN
Traumatic brain injury (TBI) is a serious health concern, yet there is a lack of standardized treatment to combat its long-lasting effects. The objective of the present study was to provide an overview of the limitation of conventional stem-cell therapy in the treatment of TBI and to discuss the application of novel acellular therapies and their advanced strategies to enhance the efficacy of stem cells derived therapies in the light of published study data. Moreover, we also discussed the factor to optimize the therapeutic efficiency of stem cell-derived acellular therapy by overcoming the challenges for its clinical translation. Hence, we concluded that acellular therapy possesses the potential to bring a breakthrough in the field of regenerative medicine to treat TBI.
Lay abstract Traumatic brain injury (TBI) is a devastating disorder that can lead to lifelong disability. Due to the complexity of TBI, to date, there is no effective and specific treatment available, other than preventive measures or intensive care to minimize the rate of mortality. Though increasingly evident studies have reported the effective role of stem cells therapy to treat TBI. However, direct exposure to stem cells has its limitation. Therefore, this study aimed to present an overview of the challenges associated with commonly used stem-cell therapy and to discuss and establish the ground for novel cell-free therapy in light of previously reported research. We hope this review will help to understand the role of cell-free therapy stem cells in the treatment of head injury and pave the way for the development of future treatments.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Células Madre Mesenquimatosas , Lesiones Traumáticas del Encéfalo/terapia , Humanos , Medicina Regenerativa , Trasplante de Células MadreRESUMEN
Learning and memory impairment is a common clinical symptom of aging and nervous system injuries, and seriously affects quality of life. Memory impairment is associated with increased oxidative stress (OS) and inflammatory response. ß-hydroxybutyrate (BHBA) is a water-soluble endogenous small-molecule ketone body that easily crosses the blood-brain barrier and has shown neuroprotection activities. In this study, we investigated the effects and mechanisms of BHBA on D-galactose (D-gal)-induced memory impairment in mice by in vitro and in vivo experiments. BHBA was administered intragastrically to D-gal-injured C57BL/6 mice for 42 days. Water maze performance, the morphology of the hippocampus with Nissl staining, the ACh content, OS, and inflammation status were examined. To further investigate the mechanism, hippocampal neuronal cells (HT22) were treated with BHBA with or without the SIRT1 inhibitor or small interfering RNAs against sirt1 (si-SIRT1) before incubation with D-gal. BHBA significantly improved water maze performance; increased the ACh content, SOD activity, and SIRT1 expression; and decreased AChE and LDH activity, ROS, MDA, IL-1ß, TNF-α contents, and NLRP3 expression. Further studies with the SIRT inhibitor or siRNAs against sirt1 reversed the above effects of BHBA. Collectively, BHBA inhibited hippocampal OS and the inflammation process to alleviate learning and memory impairment through activating the SIRT1 pathway in D-gal-injured mice, suggesting that BHBA could be a potential option for drug development of learning and memory impairment induced by nervous system injuries.